Pharmaceutical composition containing 3-butylamino - 4 - chloro-5-sulphamylbenzoic acids and salts thereof for the treatment of oedematous conditions and hypertension

ABSTRACT

THE INVENTION RELATES TO DIURETIC AND SALURETIC PREPARTIONS IN DOSAGE UNIT FORM, CONTAINING THE BITHERTO UNKNOWN 3-BUTYLAMINO-4-CHLORO-5-SULPHAMYL-BENZOIC ACID OR A SALT THEREOF WITH A PHARMACEUTICALLY ACCEPTABLE BASE AS THE ACTIVE COMPONENT. IF DESIRED TOGETHER WITH A HYPOTENSOR, THE DOSE OF THE DIURETIC BEING BETWEEN 10 AND 150 MG., CALCULATED AS THE FREE ACID.

United States Patent 01 3,560,617 PHARMACEUTICAL COMPOSITION CONTAINING S-BUTYLAMINO 4 CHLORO-S-SULPHAMYL- BENZOIC ACIDS AND SALTS THEREOF FOR THE TREATMENT OF OEDEMATOUS CONDI- TIONS AND HYPERTENSION Peter Werner Feit, Gentofte, and Herta Bruun, Esrom, near Graested, Denmark, assignors to Lovens Kemiske Fabrik Produktionsaktiesselskab, Ballerup, Denmark No Drawing. Filed June 4, 1968, Ser. No. 734,213 Claims priority, application Great Britain, June 5, 1967,

25,937/67 Int. Cl. A61k 27/00 U.S. Cl. 424250 15 Claims ABSTRACT OF THE DISCLOSURE The invention relates to diuretic and saluretic preparations in dosage unit form, containing the hitherto unknown 3-butylamino-4-chloro-5-sulphamyl-benzoic acid or a salt thereof with a pharmaceutically acceptable base as the active component, if desired together with a hypotensor, the dose of the diuretic being between 10 and 150 mg., calculated as the free acid.

The invention further relates to a method of treating patients suffering from oedematous conditions and hypertension with the dosage units in question, administering from 10 to 300 mg. daily of the diuretic to the patient.

The present invention relates to a pharmaceutical composition for the treatment of oedematous conditions and hypertension, to dosage units of the composition, and to methods for the treatment of oedematous conditions and hypertension.

More particularly, the invention relates to a pharmaceutical composition containing as at least one active agent a member of the group selected from 3-butylamino-4-chloro. -sulphamyl-benzoic acid and its salts with pharmaceutically acceptable inorganic or organic bases, together with auxiliary agents, and a dosage unit of the composition for the treatment oedematous conditions and hypertension.

The substance 3-butylamino-4-chloro-5-sulphamylbenzoic acid is a new compound which may be prepared, for example, by 3-amino-4-chloro-5-sulphamyl-benzoic acid being alkylated at the N-atom in the 3-position, as hereinafter described.

3-butylamino-4-chloro-S-sulphamyl-benzoic acid possesses a favourable diuretic and saluretic activity. As far as the saluretic effect is concerned, the compound causes in particular an excretion of sodium and of chlorine in approximately equivalent proportions, while the excretion of the potassium ion remains substantially normal, or is only slightly increased.

Certain chlorosulphamylanthranilic acids with diuretic and/or saluretic properties are already known. The useful therapeutical properties of 3-butylamino-4-chloro-5- sulphamyl-benzoic acid, however, are in themselves surprising as the molecular structure of this acid differs from the said known anthranilic acids as far as the positions of the substituents in the molecule are concerned, and the more surprising as it is known from the field of disulphamylaniline diuretics that changing the position of the substituents may result in loss of activity as well as in the occurrence of side-effects, such as a carboanhydrase inhibition which causes a therapeutically undesirable kaliuresis.

It has been found that among a series of 3-R-amino- 4-chloro-5-sulphamyl-benzoic acid, in which R represents alkyl, aralkyl, or a hetero radical, the 3-butylamino-4- chloro-5-sulphamyl-benzoic acid is superior in activity, which is surprising in view of the results of similar in- 3,560,617 Patented Feb. 2, 1971 vestigations within the field of chlorosulphamylanthranilic acids.

From a pharmaceutical point of view, it is a further advantage that 3 butylamino 4-chloro-5-sulphamylbenzoic acid is chemically stable under acid conditions. Thus, for instance, no discoloration or loss in activity has been observed in pharmaceutical preparations containing the free acid, which when given orally is readily resorbed through the upper part of the gastro-intestinal tract and distributed in the body.

Specifically, it is advantageous that 3-butylamino-4- chloro-5-sulphamyl-benzoic acid has proved to be outstanding in having a diuretic effect which is comparable in type and activity to that of the well known diuretic Furosemide, belonging to the group of chlorosulphamylanthranilic acids, while being much less toxic than the said compound of reference.

In order to determine the acute toxicity, doses of up to 1000 mg./kg. were injected intravenously into mice. With the highest dose, 4 out of 10 mice died within a few minutes after the injection showing spastic extensions of the hind-limbs and respiratory arrest. All mice not dying within the first hour after the injection recovered. The application of higher doses was prohibited by difficulties in preparing solutions of adequate concentrations. The acute LD is thus estimated at near to or slightly above a dose of 1000 mg./kg. intravenously, the corresponding value for Furosemide being 308 mg./kg. according to Muschaweck et al., ArZneimittel-Forsch. 14. 44, 1964.

The cronic toxicity has been investigated in animal tests, the test animals being dogs. Daily oral administration of 25 mg./ kg. of 3-butylamino-4-chloro-5-sulphamylbenzoic acid over a period of several months resulted in a pronounced dehydration in the mongrel dogs used.

Haematological examinations, performed at weekly intervals during the administration, gave values within the normal range for glucose, bilirubin, prothrombinproconvertin time, sedimentation rate, plasma proteins, alkaline phosphatase, and GO- and GP-transaminases. The number and distribution of leucocytes remained normal. Haemoglobin and erythrocyte values indicated some haemo concentration. A rise in plasma urea and a questionable increase in creatinin were noted. Plasma electrolyte values after 3 weeks medication were normal. Urine analysis showed no abnormalities. Histological examinations revealed no pathological changes.

The diuretic and saluretic activity of 3-butylamino-4- chloro-5-sulphamyl-benzoic acid was primarily determined in animal experiments in which the test animals, dogs, after a control period of 2 hours were injected intravenously with doses between 0.5 and 16 mg./kg. of the substance in the form of its sodium salt. The bladder was emptied by catheter at hourly intervals if the dogs did not void spontaneously. Besides the volume of urine, the amounts of Na, K, and Cl excreted were determined. Oral doses in the range from 1 to 16 mg./kg. were tested in the same manner.

In all experiments the diuretic efl ect was only apparent within the first 3 hours after the intravenous injection, to percent of the total excretion occurring within the first hour. For comparison purposes, Furosemide was given in the same doses. Both drugs proved to be of substantially the same diuretic potency in the range from 2 to 16 mg./ kg. and the excretion of potassium was equally low for both compounds. When administered by the oral route in doses between 4 and 8 mg./kg., a diuresis from 15 to 30 ml./kg., an excretion from 1.5 to 3.1 meq./ kg. of the sodium ion and an excretion from 0.6 to 0.9 meq./kg. of the potassium ion could be observed, whereas the corresponding values for the control animals were 2 rnl./kg.,-0.l5 meq./kg., and 0.1 meq./kg., respectively.

Thus, the 3-butylamino-4-chloro-5 sulphamyl benzoic acid causes approximately a tenfold excretion of water, and of the sodium ion, when administered in therapeutically acceptable doses.

Accordingly, it is the object of the invention to provide a pharmaceutical composition with diuretic and saluretic effect which is useful in the treatment of oedematous conditions, e.g. cardiac, hepatic, renal, lung, and brain oedema, in oedematous conditions during pregnancy, and other pathological conditions disturbing the balance of the electrolyte concentration in the body, for example in the form of an abnormal retension of the sodium ion, in the treatment of congestive heart failure, and in the treatment of hypertension.

With this object in view the compositions of the invention contain as at least one active component a member of the group consisting of 3-butylamino-4-chloro-5-sulphamyl-benzoic acid and its pharmaceutically acceptable salt with inorganic and organic bases, together with solid or liquid pharmaceutical carriers and auxiliary agents.

In the said compositions, the proportion of therapeutically active material to carrier substances can vary between 0.5% and 90%.

The compositions in question can either be worked up to pharmaceutical forms of presentation, such as tablets, pills, drages, and suppositories, or the composition can be filled in medical containers such as capsules or ampules or, as far as mixtures are concerned, these may be filled in bottles or tubes and similar containers.

Pharmaceutical organic or inorganic, solid or liquid carriers suitable for enternal and parenteral administration can be used to make up the compositions. For example, water, gelatine, lactose, starch, magnesium stearate, talc, vegetable and animal oils and fats, benzyl alcohol, gum, polyalkylene glycol, petroleum jelly, cocoa butter, lanolin or other known carriers for medicaments are all suitable as carriers here, while stabilizing agents, wetting or emulsifying agents, salts for varying the osmotic pressure, and buffers for securing an adequate pH- value of the composition, can be used as auxiliary agents.

Among suitable salts of 3 butylamino 4-chloro-5- sulphamyl-benzoic acid for use in the present compositions, mention may be made of the alkali metal salts, the alkali-earth metal salts, the ammonium salt, and salts with organic bases, such as the ethanol amine salt and the diethanol amine salt. Besides, the free acid may itself also be used in a composition according to the invention.

Thus, for preparations in the form of tablets or the like, or in injectable preparations, the sodium salt or the potassium salt may be used, being sufliciently water-soluble. For injectable preparations, however, salts with certain organic bases may advantageously be employed due to their high solubility in water.

The free acid may be administered in capsules, or in tablets, of which the latter may be effervescence tablets in order to obtain a quick resorption, or they may be sustained-release tablets in order to obtain a prolonged effect which may be desirable in the treatment of hypertension.

Besides the 3-butylamino 4 chloro-5-sulphamylbenzoic acid or a salt thereof, the compositions of the invention may contain other suitable active components in the treatment of hypertension and oedematous conditions, such as hypotensors, as hydralazin, methyldopa, reserpine and other Rauwolfia serpentina alkaloids and/ or tranquilizers, such as meprobamate.

Another object of the invention resides in the selection of a dose of the 3-butylamino-4-chloro-5-sulphamylbenzoic acid, or one of its salts, which can be administered so that the desired activity is achieved without simultaneous secondary effects. It has been found that 3- butylamino-4-chloro-5-sulphamyl-benzoic acid and its salts are conveniently administered in dosage units containing not less than mg., and preferable from to 150 mg., calculated as the free 3-butylamino-4-chloro-5- sulphamyl-benzoic acid.

The term dosage unit as used here is meant to cover a single dose capable of being administered to the patients, which may be readily handled and packed, remaining as a physically stable unit dose comprising either the active material as such, or a mixture of it with solid or liquid pharmaceutical diluents or carriers.

If the composition is to be injected, a sealed ampul, a vial or a similar container may be provided, containing as a dosage unit a parenterally acceptable aqueous or oily injectable solution or dispersion of the active material.

It is still another object of the invention to provide a method of treating patients suffering from oedematous conditions and hypertension, the method comprising administering to the patient from 10 to 300 mg. per day of 3-butylamino 4 chloro-5-sulphamyl-benzoic acid or a corresponding dose of one of its salts with pharmaceutically acceptable bases. Preferably, the compound is given in the form of the dosage unit aforesaid.

For oral administration, the dosage unit may conveniently contain from 20 to 150 mg. of the 3-butylamino-4-chloro-5-sulphamyl-benzoic acid, as such or in the form of one of its salts, in the form of tablets, pills, or capsules to be given at suitable intervals, for instance once, twice, or thrice daily, always depending, however, on the patient and his condition. Preferably the tablets contain from 30 to 100 mg. each of the 3-butylamino-4- chloro-5-sulphamyl-benzoic acid or one of its salts. If the dosage unit is injectable, the unit will conveniently consist of from 10 to 50 mg. of the 3-butylamino-4-chloro- 5-sulphamyl-benzoic acid, dissolved in an aqueous solvent, the said dosage unit for instance being enclosed in an ampule containing 2 ml. of 1 percent aqueous solution of the sodium salt of 3-butylamino-4-chloro-5-sulphamylbenzoic acid.

The parenteral preparations are in particular useful in the treatment of conditions in which a quick dehydration is desirable, e.g. in the intensive therapy in the case of oedemas in the lung. In the continuous therapy of patients suffering from e.g. hypertension, the tablets or capsules may be the appropriate form of pharmaceutical preparation owing to the prolonged effect obtained when the drug is given orally.

In the treatment of heart failure and hypertension such tablets may advantageously contain other active components, as specified hereinbefore.

Thus for instance such tablets may contain each 40 mg. of the 3-butylarninc-4-chloro-5-sulphamylbenzoic acid or one of its salts in combination with hydralazine in amounts from 10 to 50 mg. or reserpine in amounts from 0.05 to 0.5 mg. or methyldopa in amounts from 100 to 500 mg., and furthermore the tablets may contain, as a tranquilizer, meprobamate (2:2-di(carbamoyloxymethyl)-pentane) in amounts from 100 to 400 mg., preferably at least 150 mg. and not more than 250 mg.

A method of producing 3-butylamin0-4-chloro-5-sulphamyl-benzoic acid and salts thereof will be described in details in the following.

(a) 5-chlorosulphonyl-4-chloro-3-nitro-benzoic acid To a mixture of 250 ml. of concentrated H and 160 ml. of concentrated HNO a solution of 114 g. of 4-chloro-3-chlorosulphonyl-benzoic acid in 620 ml. of concentrated H 80 was added with stirring over a period of 1 hour. The temperature was then raised to C., and the reaction mixture was stirred for an additional 6 hours. After cooling, the mixture was poured onto ice, and the precipitate was filtered off and washed with water. After drying and recrystallization, 91 g. of 5-chlorosulphonyl-4-chloro-3-nitro-benzoic acid were obtained with M.P. 193-l94 C. (dccomp.).

(b) 4-chloro-3-nitro-5-sulphamyl-benzoic acid g. of 5-chlor0sulphonyl-4-chloro3-nitro-benzoic acid were slowly added to ml. of concentrated aqueous ammonia (25% NH with stirring and cooling. After 2 hours of stirring, the excess ammonia was removed in vacuo, and the precipitated ammonium salt of 4-chloro- (f) Calcium salt of 3-butylamino-4-chloro-5- 3-nitro-5-sulphamyl-benzoic acid was collected by filtrasulphamyl-benzoic acid tion and Washed with ice-water. The moist filter cake was dissolved in 300 ml. of boiling 4 N hydrochloric acid. The resulting solution was cooled, and the precipitated 4-chloro-3-nitro-5-sulpharnyl-benzoic acid was filtered off and washed with water. After recrystallization from water and subsequent drying, 60 g. of the acid were obtained with M.P. 235-2365 C. (decomp.).

(c) 3-amino-4-chloro-S-sulphamyl-benzoic acid 1 3.07 g. of 3-butylamino-4-chloro-5-sulphamyl-benzoic acid were dissolved in 50 ml. of 0.2 N LiOH. Addition of 2.5 ml. of a saturated CaC1 solution precipitated the calcium salt. The salt was collected by filtration and dried in air. The salt crystallized with 3 moles water of crystallization.

(g) Potassium salt of 3-butylamino-4-chloro-5- sulphamylbenzoic acid 15.35 g. of 3-butylamino-4-chloro-5-sulphamyl-benzoic acid were suspended in ml. of boiling water. 2 N KOH was added until a clear solution of pH 7.5 was reached.

15 After cooling, the precipitated potassium alt was filtered off and dried at 120 C.

A mixture of 67 g. of iron powder, 6.4 g. of ammonium chloride, and 200 ml. of water was heated to 70 C. 0.5 ml. of concentrated hydrochloric acid were added, and the mixture was heated on a steam bath with stirring, 57 g. of 4-chloro-3-nitro-S-suIphamyI-benzoic acid being m ppmons Y a penod of 2 hours f The following, non-limiting examples serve to illustrate tronal heating and stirring for 14 hours, the reaction mrxthe preparation of the com ositions of the invention ture was cooled and filtered by suction. The moist filter p cake was suspended in 100 ml. of water, and by the addi- EXAMPLE I tion N Sodmm hydroxlde the PH was adlusted Capsules containing the free 3-butylamino-4-chloro- The mixture was filtered, and the process repeated with s sulphamyl benzoic acid the filter cake. The combined filtrates were acidified to Ingredients: G. a pH of 2 to 3, and the precipitated acid was collected Micronized 3 butylamino 4 ch1or0 by suction and washed with water. After recrystallizaamylbenzoic acid 60 tion from water and subseq nt y g, 40 of 0 Lactose "11:11:11 T 300 4-chloro-5-sulphamyl-benzoic acid were obtained with Talc M.P. 261-2615 C. 15 The lngredrents were mixed and passed through a 60 (d) 3 b 1 i .4- h1 .5- 1 h 1 b i id mesh per linear inch sieve and subsequently further mixed for 15 minutes. The mixture was filled into No. 1 gel- A suspension of 10 g. of 3-a-mino-4-chloro-5-sulphamylatine capsules (Parke, Davis and Co.) using a semi-autobenzoic acid in 75 ml. of n-bu-tanol containing 0.1 g. of pmatic capsule-filling machine shaken by vibrator. Each toluenesulphonic acid was refluxed, while the water formed Capsule contains 250 mg. of the mixture corresponding by the esterification process was simultaneously removed to 1500 capsules each of mg. of the free 3butylaminoby azeotropic destillation. To the clear solution of the 39 4-chloro-5-sulphamyl-benzoic acid. resulting butyl 3-amino-4-chloro-5-sulphamyl-benzoate, The effect of the compositions was tested as follows: 9.1 g. of butyl-p-toluene-sulphonate were added, and the Five healthy persons received each 2 capsules correreaction mixture was further boiled for 96 hours under sponding to 80 mg. of the drug, whereafter the urinary reflux. Then the butanol was removed by evaporation in excretion was observed for 24 hours. The average effect vacuo. The residue was dissolved in 80 ml. of 2 N aqueous appears from the following table.

DIURETIC AND SALURETIO EFFECT OF 3-BUTYLAMINOA-CHLORO-5SULPHAMYL-BENZOIC ACID Urinary excretion 06 hours, 6-24 hours and 0-24 hours Volume (ml.) Sodium (meq.) Chloride (meq.) Potassium (n1eq.)

Mg. o-e 6-24 0-24 0-6 e-24 0-24 0-6 6-24 24 (H; 6 24. 0-24.

Control 0 429 604 1, 033 33 5s 91 32 62 94 17 25 42 Drug 80 1,083 446 1, 529 121 29 150 145 28 173 24 23 47 sodium hydroxide and the solution was heated on a steam EXAMPLE 11 bath for 1 hour. The mixture was cooled and extracted with diethyl ether. From the aqueous layer, the sodium Tabl ts containing free 3-butylamino-4-chlorosalt of 3-butylarnino-4-chloro-5-sulphamyl-benzoic acid i-sulphamylbenzoic acid crystallized after the pH had been adjusted to 7.5 by addition of 4 N hydrochloric acid. The salt was filtered Ingredients: G. off, and washed with water. 3 g. of the sodium salt were 3-bu'fylamino 4 Chloro-5-sulphamyl-benloic dissolved in 30 ml. of hot water, 2 ml. of acetic acid acld 120 were added, and the precipitated 3butylamino-4-chloro- Corn Starch 285 S-sulpharnyl-benzoic acid was filtered ofi from the cooled Lactose 300 solution, yielding the pure compound with M.P. 238- Talc 45 240 1 The ingredients were mixed and screened through a Dlethanolamme Salt of f l 20 mesh per linear inch sieve and subsequently treated sulphamyl'benzolc and with an aqueous solution of gelatine (4 percent) in sufli- 3.07 g. of 3-butylamino-4-chloro-5-su1phamy1-benzoi cient amount to form a granulate. The granulate was acid were dissolved in 25 ml. of hot butanol, and a soludried and broken 0 a 16 m sh per linear inch sieve. Aftion of 1.0 g. of diethanolamine in 10 ml. of butanol was ter addition of talc the granulate was compressed into added. After cooling, the precipitated diethanolamine salt ta l ts of 250 mg. using 9 mm. punches and dies, yieldwas collected by filtration to yield the pure salt with M.P. ing 3000 tablets each containmg 40 mg. of the free 3- 105 C. butylamino-4-chloro-5-sulphamyl-benzoic acid.

7 EXAMPLE 111 Tablets containing the potassium salt of 3-butylamino-4-chloro-5-sulphamyl-benzoic acid Ingredients: G. 3-butylamino-4-chloro-5-sulphamyl-benzoic acid as the potassium salt 125 Lactose 625 Corn starch 750 The potassium salt was mixed with the other ingre dients and granulated after moistening with a 10 percent aqueous solution of polyvinylpyrrolidone.

The granulate was dried and broken on a 16 mesh per linear inch sieve. After addition of 100 g. talc and 10 g. of magnesium stearate, and mixing, the mixture was compressed into tablets using 10 mm. punches and dies, yielding tablets of 340 mg. and containing 43 mg. of 3-butylamino-4-chloro-5-sulphamyl-benzoic acid each.

EXAMPLE IV Ampules containing the sodium salt of 3-butylamino-4-chl0ro-5-sulphamyl-benzoic acid Ingredients: G. 3-butylamino 4 chloro--sulphamyl benzoic acid 10.0 Sodium hydroxide 1.3 Sodium chloride 4.0

Sterile water up to 1000 ml.

The ingredients were dissolved in the water, and the solution was sterilized by filtration. The sterile solution was thereafter filled into ampules under aseptic conditions, yielding 500 ampules of 2 ml. each.

EXAMPLE V Tablets containing 3-butylamino-4-chloro-5-sulphamylbenzoic acid as its potassium salt, and reserpine Ingredients: G.

3-butylamino-4-chloro 5 sulphamyl-benzoic acid as the potassium salt 430 Reserpine 0.1 Lactose 1249 Corp starch 1500 The reserpine was triturated with 100 g. of lactose, and the mixture was forced through a 30 mesh per linear inch sieve. Thereafter the other ingredients were incorporated, and the mixture was granulated with sufficient ethly alcohol/ water (60 percent). The granulate was dried and broken on a 16 mesh per linear inch sieve. After addition of 200 g. of talc and 20 g. of magnesium stereate, and mixing, the mixture was compressed-into tablets using mm. punches and dies, yielding tablets of 340 mg. containing 40 mg. of 4-butylamino-4-chloro- S-sulphamyl-benzoic acid and 0.1 mg. of reserpine.

In a similar manner, tablets were prepared which contained 40 mg. of 3-butylamino-4-chloro 5-sulphamyl-benzoic acid as the free acid, and 10 mg. of hydralazine.

EXAMPLE VI Capsules containing 3-butylamino-4-chloro-5-sulphamylbenzoic acid and methyldopa Ingredients: G. 3-butylamino-4-chloro 5 sulphamyl-benzoic acid 80 Lactose 100 T ale D,L-methyldopa 200 The ingredients were mixed and passed through a 60 mesh per linear inch sieve. The resultant mixture was subdivided and formed into capsules each containing mg. of the free 3-butylamino-4-chloro-S-suIphamyl-benzoic acid and 100 mg. of D,L-methyldopa.

What we claim is:

1. A pharmaceutical preparation in dosage unit form for the treatment of patients suffering from oedematous conditions and hypertension, comprising as at least one active component a member of the group consisting of 3- butylamino-4-chloro-5-sulphamyl-benzoic acid and its non-toxic salts together with a non-toxic pharmaceutically acceptable carrier, the quantity of the said active component in the uint being between 10 and 150 mg., calculated as the free 3-butylamino-4-chloro-5-sulphamylbenzoic acid.

2. A pharmaceutical preparation in oral dosage unit form according to claim 1. in which the units contain from 10 to 150 mg. of an alkali metal salt S-butylamino- 4-chloro-5-sulphamyl-benzoic acid.

3. A pharmaceutical preparation in oral dosage unit form according to claim 1, in which the units contain from 10 to 150 mg. of the free 3-butylamino-4-chl0ro-5- sulphamyl-benzoic acid.

4. A pharmaceutical preparation in dosage unit form according to claim 1, which contains, as a diuretic, a member of the group consisting of 3-butylamino-4-chloro- 5-sulphamyl-benzoic acid and its non-toxic salts, and as a hypotensor a Rauwolfia serpentina alkaloid with hypotensive activity, together with a non-toxic pharmaceutically acceptable carrier, the quantity of the diuretic being 10 to 150 mg. calculated as the free 3-butylamino-4- chloro-S-sulphamyl-benzoic acid, and the quantity of hypotensor being between 0.05 and 0.5 mg.

5. A pharmaceutical preparation in dosage unit form as claimed in claim 4, which also contains 2:2-di(carbamoyloxymethyl)-pentane in an amount between and 400 mg.

6. A pharmaceutical preparation in dosage unit form according to claim 1, which contains, as a diuretic, a member of the group consisting of 3-butylamino-4-chloro- 5-sulphamyl-benzoic acid and its non-toxic salts, and as a hypotensor hydralazine, together with a non-toxic pharmaceutically acceptable carrier, the quantity of the diuretic being between 10 and mg. calculated as the free 3-butylamino-4-chloro-5-sulphamyl-benzoic acid, and the quantity of hydralazine being between 5 and 50 mg.

7. A pharmaceutical preparation in dosage unit form as claimed in claim 6, which also contains 2:2-di(carbamoyloxymethyl)-pentane in an amount between 100 and 400 mg.

8 A pharmaceutical preparation in dosage unit form according to claim 1, which contains, a a diuretic, a member of the group consisting of 3-butylamino-4-chloro- 5-sulphamyl-benzoic acid and its non-toxic salts, and as a hypotensor methyldopa, together with a non-toxic pharmaceutically acceptable carrier, the quantity of the diuretic being beween 10 and 150 mg. calculated as the free 3-butylamino-4-chloro5-sulphamyl-benzoic acid, and the quantity of methyldopa being between 100 and 500 mg.

9. A pharmaceutical preparation in dosage unit form as claimed in claim 8, which also contains 2:2-di(carbamoyloxymethyl)-pentane in an amount between 100 and 400 mg.

10. An injectable pharmaceutical preparation in dosage unit form, in which the units contain from 10 to 50 mg. of 3-butylamino-4-chloro-5-sulphamyl-benzoic acid in the form of a non-toxic salt, dissolved in an aqueous medium.

11. The method of treating patients suffering from oedematous conditions and hypertension, which comprises administering to the patient from 10 to 300 mg. per day of a member of the group consisting of 3-butylamino-4-chloro-5-sulphamyl-benzoic acid and its nontoxic salts.

12. A method as claimed in claim 11, which comprises the oral administration of an alkali metal salt of 3- butylamino-4-chloro-5-sulphamyl-benzoic acid in the formof tablets.

13. A method as claimed in claim 11, which com- References Cited UNITED STATES PATENTS 3,050,553 8/1962 Novello 424-319 5 SAM ROSEN, Primary Examiner U.S. Cl. X.R.

5-sulphamy1-be'nzoic acid in doses from 10 to 50 mg. 10

per day. 

